Development of PAR2 Pepducins for the Treatment of COPD

Chronic obstructive pulmonary disease (COPD), which includes chronic bronchitis and emphysema, afflicts 16 million Americans and is the third leading cause of disease-related death in the US. The standard-of-care treatment for COPD lung disease is typically symptomatic relief with bronchodilator therapy. As leukocyte infiltration is the crux of the disease, patients are also treated with anti-inflammatory drugs that suppress tissue damage and cytokine release. However, major challenges remain with use of immunosuppressants which increase the risk of pneumonia and other side effects, and generally leave the patient with a poor quality of life with diminishing lung function, not to mention high cost. Therefore, new disease-modifying treatment options are in great demand for COPD patients. Oasis Pharmaceuticals and their collaborators at Tufts Medical Center have focused their efforts on a novel target—Protease-Activated Receptor-2 (PAR2), recently discovered as an important mediator in the pathogenesis of COPD. PAR2 is a major cell surface receptor for elastase and other proteases that are upregulated in lung bronchial and alveolar epithelial cells, mucus-producing goblet cells, and inflammatory cells during progression of COPD. The cell-penetrating, lipidated PAR2 inhibitor OA-235i, was developed using our proprietary PepducinTM technology. PepducinTM technology offers a unique opportunity to target the intracellular surface of recalcitrant G-protein coupled receptors (GPCRs) such as PAR2 with exquisite specificity, potency and long half-lives, with prolonged drug exposure to the target tissue, namely lung. OA-235i is an advanced drug candidate that blocks damaging PAR2 signaling in preclinical models of COPD. Oasis Pharmaceuticals successfully formulated and produced cGMP OA-235i at 98% purity and high stability. In pilot in vivo efficacy studies, OA-235i significantly reduced emphysema and inflammation in elastase-COPD models by ≥50%. OA-235i was safe and tolerated in 28-day repeat dose GLP toxicology studies in two species with no evidence of organ toxicity or any laboratory abnormalities at high multiples of the therapeutic dose. Phase I will validate the therapeutic potential of daily through once-weekly OA-235i in COPD models and in tissue culture and characterize PAR2 inflammatory responses in primary tissues from COPD patients and healthy controls. The final milestone will be to conduct a preIND meeting to design a first-in- COPD patient clinical trial of repeat dose OA-235i with the FDA Division of Pulmonary, Allergy and Critical Care (DPACC). The translational studies in this application will therefore provide a rapid preclinical validation and accelerate the commercialization of OA-235i for the treatment of COPD patients.